Systems and methods for intra-oral drug delivery

ABSTRACT

Systems and methods are disclosed for intra-oral delivery of drugs.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.11/982,301, filed Oct. 31, 2007, now U.S. Pat. No. 8,075,309, which is acontinuation of U.S. patent application Ser. No. 11/000,282, filed Nov.30, 2004, now abandoned, the entire contents of which are herebyincorporated by reference.

BACKGROUND

The present invention is related to systems and methods for intra-oraldrug delivery. As noted in commonly owned U.S. Pat. No. 6,607,382entitled “Methods and systems for concurrent tooth repositioning andsubstance delivery,” the content of which is incorporated herewith, therepositioning of teeth may be accomplished with the use of a series ofremovable elastic positioning appliances such as the Invisalign® systemavailable from Align Technology, Inc., the assignee of the presentinvention. Such appliances have a thin shell of elastic material thatgenerally conforms to a patient's teeth but is slightly out of alignmentwith an initial or immediately prior tooth configuration. Placement ofthe elastic positioner over the teeth applies controlled forces inspecific locations to gradually move the teeth into the newconfiguration. Repetition of this process with successive appliancescomprising new configurations eventually moves the teeth through aseries of intermediate configurations or alignment patterns to a finaldesired configuration. A full description of an exemplary elasticpolymeric positioning appliance is described in U.S. Pat. No. 5,975,893,and in published PCT application WO 98/58596, the content of thesedocuments are incorporated by reference for all purposes.

The appliance is effective in repositioning teeth when it is placed overthe patient's teeth. Removal of the appliance for any reason interruptsthe treatment plan and lengthens the overall period of treatment.Therefore, removal of the appliance should be minimized for effectiveand timely treatment. However, a number of dental and periodontaltherapies which may be desired or required by the patient may not beeffectively utilized while the appliance is in place. Such therapies maybe prescribed by a practitioner to improve oral health or they may berequested by the patient for cosmetic purposes.

The '382 patent discloses devices, systems and methods for orthodontictreatment using elastic repositioning appliances while concurrentlyproviding dental and periodontal therapies. Such therapies aretraditionally provided with the use of a variety of accessories anddevices which are applied when the repositioning appliance is removedfrom the patient's mouth. The '382 system eliminates the need for suchremoval and additional devices by incorporating these therapies into therepositioning appliance. United States Patent Application 20040115587,the content of which is incorporated herewith, discloses an orthodontictreatment involving applying force to reposition teeth and administeringa tissue remodeling and/or an angiogenic substance(s) to the periodontaltissue surrounding the teeth to be moved. The substance(s) may bedelivered before, during, or after the teeth are moved, and thesubstance(s) may be selectively applied only to those teeth undergoingmovement at any particular time. The substance(s) may be applied fromthe dental repositioning appliance or may be applied separately, eithertopically or by injection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplary method for intra-oral delivery of a substanceto an individual.

FIGS. 2A-2B are exemplary removable appliances adapted to fit over teethon a jaw.

FIG. 2C shows a cross-sectional view of the appliance of FIG. 2B on anexemplary tooth.

FIG. 2D is a cross sectional view of FIG. 2C without the tooth and gumline.

FIGS. 2E-2F show additional embodiments of appliances for delivery ofdrugs or agents.

FIG. 3 illustrates another drug delivery system.

FIGS. 4A-4E illustrate various views of a bracket with a reservoir.

FIGS. 5A-5E show various embodiments of drug delivery systems.

FIG. 6A illustrates an embodiment where energy is applied to anappliance to effect teeth movement or drug delivery.

FIG. 6B illustrates an embodiment where energy is applied to wires toeffect teeth movement or drug delivery.

SUMMARY

Systems and methods are disclosed for intra-oral delivery of drugs.

Advantages of the system include one or more of the following. Thesystem enables drugs or therapeutic agents to be delivered through themouth. The system provides ideal drug delivery for certain diseasesrelating to periodontics, tooth surface, endodontics, and diseasesassociated with cancer and medical conditions.

For dental diseases, the system is placed so that release of thetherapeutic agent occurs in the immediate vicinity of the diseaseprocess. As the volume of distribution is limited to the volume of gumpocket or crevice, relatively high concentrations of therapeutic agentcan be delivered by devices with small therapeutic agent reservoircapacities. The small amount of therapeutic agent required under theseconditions, typically a few milligrams, greatly reduces the effect ofthe therapeutic agent at distal sites within the body, thereby greatlydecreasing the potential for systemic side effects. Thus, a high degreeof effectiveness is achieved using a relatively small amount of drug.

DESCRIPTION

Appliance for Drug Delivery

FIG. 1 shows an exemplary method for intra-oral delivery of a substanceto an individual such as a patient, for example. The substance can be adrug or a bio-active agent, among others. The process of FIG. 1 includesattaching the substance to an oral structure (10) and allowing thesubstance to intra-orally interact with the body of the individual (12).In one embodiment, the substance is fluidly provided from the oralstructure into the body at a predetermined rate. The substanceeventually affects or alters the individual's physiology in a desiredmanner (14). The term “oral structure” refers to all areas within themouth, including teeth, gingiva, cheeks, gums, lips, tongue, thorax,back of the throat, and beneath the tongue.

The method of FIG. 1 thus attaches the substance to an oral structureusing a suitable dental device; and fluidly providing the substance fromthe oral structure into a body at a pre-selected dose. The substance canaccelerate or decelerate tooth movement.

The substance can induce irritation of the oral structure or can induceinflammation of a bone structure. The pattern or sequence of irritationor inflammation can be varied. For example, the pressure, timing,location, degree of irritation or inflammation, and the depth of theirritation or inflammation can be varied.

The substance can be positioned on a bracket, a dental attachment, abracket auxiliary, a ligature tie, a pin, a bracket slot cap, a wire, ascrew, a micro-staple, a denture, a partial denture, a dental implant, aperiodontal probe, a periodontal chip, a film, or a space between teeth.The substance can also be positioned on a removable appliance, and oneor more modules may be positioned on the removable appliance to housethe substance. The substance can provide energy for treatment, forexample electric, light, heat, sound, magnetic or electromagneticenergy. The oral structure can be recharged with an additional amount ofthe same or different substance.

In one embodiment, the physical volume or shape of the substance iscomputer designed to support a precise delivery of the substance. Acomputer system can scan a patient's dentition; and design one or moreappliances to attach the substance to the oral structure based on thescanned dentition. At least one of the appliances is designed todispense the preselected dose. Moreover, the appliances can dispense thesubstance in a predetermined sequence. For example, at least two of theappliances can dispense the substance in two different dosages fordelivery at two different periods. Thus, for birth control drugs, morecan be delivered on day 15 and less can be delivered on day 30, forexample.

The system can perform diagnostics as well. To do this, the systemsamples an intra-oral substance; and detects a body condition (such as adisease) based on the intra-oral substance. A processor can receive thesampling result and performs a close-loop delivery of substance based ona sampled intra-oral substance, as discussed in more detail below. Thesystem can also transmit the detected body condition to a remotecomputer for diagnosis.

The substance can be any known chemical substance. Preferably, thesubstance is a medical grade drug, chemical agent, or a bioactive agent.Examples of the drug or agent can include antibacterials, antibiotics,anti-inflammatory agents, immune-suppressive agents, immune-stimulatoryagents, dentinal desensitizers, odor masking agents, immune reagents,anesthetics, nutritional agents, antioxidants, lipopolysaccharidecomplexing agents, and peroxides, among others.

The attachment of the substance to the oral structure can be donethrough a removable appliance, a fixed appliance such as a bracket, adental attachment, a wire, a screw, a tap, a micro-staple, a dentalimplant, a perioprobe, a periochip, a film or composite material, or aspace between teeth, among others.

The tooth is held firmly in place by the cementum, periodontal ligament,alveolar bone and gingiva. These connective tissue structures containcollagen and elastin fibers crosslinked into a supporting matrix.Additional components of this matrix include glycosaminoglycans (GAGs)and proteoglycans which play a role in resisting compressive forces intissues. The architecture of this matrix can shift over time in responseto a constant pressure that stimulates matrix breakdown, matrixresynthesis and remodeling of the tissue. To accelerate tooth movement,agents increase the rate of matrix degradation during the period inwhich force is applied to the tooth.

FIG. 2A shows an exemplary removable appliance 15 adapted to fit overteeth on a jaw 16. The appliance can be coated with a drug, chemicalagent, or a bioactive agent. In one embodiment, the drug is inactiveuntil contact with water or saliva. Alternatively, release of the agentcan be stimulated by water or by saliva. Thus, in one case, uponwearing, saliva activates the drug/agent and allows the drug/agent toseep out and treat the patient through the oral cavity of the patient.The substance can also be delivered through the patient's gingiva.

The appliance can release the agent to the oral environment when theappliance is placed over the teeth. Such means may comprise a layerwhich includes the agent. The layer may be formed over at least aportion of the surfaces of the repositioning appliance. These surfacesinclude both the cavity surfaces, the surfaces within the cavities whichcontact the teeth when in place, and the external surfaces, the surfacesof the appliance which contact the cheeks and lips when in place. Thelayer may be comprised of various materials and may take a variety offorms. For example, the layer may consist essentially of the agent. Inother words, the agent may be attached directly to a surface of thepolymer shell of an elastic repositioning appliance. This may beachieved by applying the agent (optionally in an inert carrier ordiluent) itself to the surface utilizing a number of methods, such asspraying, painting and/or dipping. When the repositioning appliance isplaced over the patient's teeth, the agent may then be released to theoral environment.

Alternatively, the layer may comprise the agent present in or on acarrier or binder which promotes adhesion or attachment to the applianceand/or which creates a matrix from which the agent can be released bydiffusion or dissolution. In one embodiment, the agent is dissolved inthe carrier or binder. In this case, the agent may be provided in powderor similar form and dissolved in a liquid solvent. The result may be asolution which may be applied to a surface of the shell, typically byspraying, painting and/or dipping, to form a coating or film. When therepositioning appliance is placed over the patient's teeth, the agentmay then be released from the coating to the oral environment. Releasemay be due to activation or deactivation of the carrier or any otherreleasing mechanism, such as by enzymes or proteins in saliva. Orrelease may be due to degradation of the carrier by contact with, forexample, saliva. In some cases, the binder or carrier may evaporate uponapplication to the layer to the surface leaving the agent behind. Inthese cases, the agent may be released in a similar fashion as when theagent is directly attached to the surface, as described above. It may beappreciated that any agent, particularly fluoride materials,antibiotics, bleaching materials and breath fresheners, may be deliveredto the oral environment in this manner.

In another embodiment, the agent is encapsulated or suspended in thelayer. A common material for suspension of an agent is a semisolidmaterial, such as a gel, jelly or putty. Such a material may be appliedto a surface of the shell by spraying, painting and/or dipping to form acoating or film. Here, as in all cases, suspension is not limited to ascientific definition and may refer to any situation in which a carrierholds, contains, supports or otherwise includes an agent. Alternativelyor in addition, the semisolid material may be deposited in the cavitiesof the polymer shell which are shaped to receive the teeth. The cavitiesmay be filled to any desired level. When the repositioning appliance ispositioned over the teeth, the teeth will directly contact the semisolidmaterial in the cavities and displace any extra material as the teethare inserted into the cavities. Therefore, it is desired to fill thecavities to a level which will avoid excess overflow of the materialfrom the appliance. Delivery of an agent by use of a semisolidsuspension material is common in bleaching treatments and fluoridetreatments, for example. However, such treatments apply the materialwith the use of a tray or generic appliance which does not applyrepositioning forces to the teeth. By modifying a repositioningappliance, as described above, orthodontic treatment may continuethroughout the delivery of such agents. It may be appreciated that anyagent, particularly fluoride materials, antibiotics, bleaching materialsand breath fresheners, may be delivered to the oral environment in thismanner.

Another common material for encapsulation or suspension of an agent is acontrolled-release material. Thus, the layer may be comprised of arate-controlling material wherein the rate controlling material controlsthe rate at which the agent is released from the layer.Controlled-release or rate-controlled materials deliver a predeterminedamount of an agent at a predetermined rate. Often such deliverymaintains a steady-state concentration of an agent in an environmentwithin a desired therapeutic range for a prolonged period of time. Thus,a prescribed dosage may be delivered. In addition, the ability tosustain delivery eliminates the need for repeated applications of theagent for dosed delivery to the oral environment.

Although such controlled release materials may be provided as asemisolid material, such as a gel, jelly or putty, as described above,these materials may also be provided as a solid material which isattached to the polymeric shell of the repositioning appliance. One typeof controlled-release material comprises a polymer matrix membranewithin which finely dispersed particles of an agent are suspended. Theagent may diffuse through the matrix membrane according to aconcentration gradient. Alternatively or in addition, the agent may bereleased by degradation of the polymer matrix membrane material. Ineither case, the controlled-release material may be provided as a sheetwhich may be laminated to a surface of the shell. The controlled-releasesheet may be layered with the elastomeric polymer and vacuum formed overa mold to form the repositioning appliance. The controlled-releasematerial may be arranged so that it is present on the inside or outsidesurfaces of the appliance depending on the material and desiredapplication. Or, the controlled-release sheet may be laminated or bondedto a surface of the polymeric shell after forming to supply agentdelivery in desired areas. Alternatively, the controlled-releasematerial may be provided as a tablet or similar mass which may beinserted into the polymeric shell of the repositioning appliance. Theagent may then elute from the tablet into the oral environment overtime.

In another embodiment, the agent may be held within pores of a materialand may elute out at a controlled rate from the pores. The agent itselfmay be absorbed into the pores of the material, or the agent may besuspended in a carrier which is absorbed into the pores of the material.In the latter case, the agent may be released from the carrier bydiffusion and/or by controlled degradation of the carrier material. Thismay incorporate a rate-controlling mechanism in addition to thecontrolled-release of the agent from the pores. As mentioned, in somecases, enzymes in the patient's saliva will activate the release ordegrade the carrier material to release the agent. It may be appreciatedthat the agent may be released by a combination of any of the releasemethods.

In a further embodiment, the polymeric shell of the repositioningappliance itself comprises a controlled-release material containing theagent. In this case, at least a portion of a polymeric shell is formedfrom a controlled release material wherein the rate controlling materialcontrols the rate at which the agent is released from the shell. Aspreviously described, the controlled-release material may be provided inthe form of a sheet. Thus, the sheet of controlled-release material maybe vacuum formed over a mold of the patient's teeth to form arepositioning appliance itself. In this manner, no additionalelastomeric materials may be needed to form the appliance. Thecontrolled-release material may be a polymer matrix membrane, a porousmaterial or any suitable material. Controlled-release may be designed sothat the elution rate of the agent corresponds to the repositioning rateof the teeth. The agent may elute throughout the repositioning process,concluding as the teeth reach the desired arrangement prescribed by theappliance.

In another embodiment, the appliance is made from a polymeric materialthat exhibits reduced stress relaxation and creep when used as a toothpositioner in the oral cavity. Tooth positioners are made from polymericmaterials. Once fabricated the tooth positioners are coated with a thinlayer of a polymeric material. This coating serves to protect the toothpositioner from the potentially harmful environmental effects ofsalivary components, water and temperature. The physical properties ofthe polymeric coating (e.g, durometer, lubricity, elasticity, etc.) maybe adjusted by modifying the polymer chemistry. Furthermore, a widevariety of substances may be combined with the polymeric coatingsolution to provide ancillary patient benefits. For example, flavorantsmay be combined with the polymeric coating and released over time tohelp control oral malodor. Drugs to control gingivitis or treatperiodontal disease may also be combined with the polymeric coating.Finally, biocompatible dyes or colorants contained in the polymer matrixmay be released when exposed to salivary fluids. The gradualdisappearance of the colorant may signify whether or not the toothpositioner is being worn by the patient. The polymeric coatings appliedto the dental appliance serve as a protective barrier to the harmfuleffects of salivary components, temperature and water and can containflavorants, dyes, polymers, surface active molecules, antimicrobialagents and drugs.

In a still further embodiment, the releasing means coupled to at leastsome of the repositioning appliances comprises a reservoir formed in theshell of the appliance in addition to the cavity which receives theteeth. Typically, a rate controlling membrane is disposed over thereservoir wherein the rate controlling membrane controls the rate atwhich the substance is released from the reservoir. The reservoir may bepre-filled or preloaded with an agent or substance for delivery. In thiscase, the appliance may be ready for insertion or use upon removal fromany packaging without the need of loading the appliance with the agentfor delivery. If the releasing means is designed for a single deliveryperiod, the appliance may be worn throughout the prescribedrepositioning period and then disposed of. If the releasing means isdesigned for multiple delivery periods, the reservoir may be replenishedwith the agent to be released any number of times throughout theprescribed repositioning period. It may be appreciated that any agent,particularly fluoride materials, antibiotics, bleaching materials andbreath fresheners, may be delivered to the oral environment in thismanner.

In some instances, it may be desirable to change a visual characteristicof the polymeric shell of an oral appliance. Such appliances comprise apolymeric shell having a cavity shaped to be removably placeable overthe teeth and a material on or within the shell that changes a visualcharacteristic of the shell. Such a change is typically in response to achange in the environment. In some cases, the visual characteristic is acolor, such as green, red or blue. Thus, the appliance may appearcolored or a particular color under certain environmental conditions,either in the oral environment or when removed. The described materialmay be a dye which changes color in response to a change in temperature.For example, the dye may change color when the appliance is removed fromthe mouth and changes temperature from body temperature (37° C.) to roomtemperature (25° C.). Similarly, the dye may change color when theappliance is rinsed with cool water.

The appliance can be used to provide an intra-oral drug delivery system.In addition to the drugs described above, other compounds can be used aswell. For example, a drug coated appliance can be used to deliverdesensitizing medication to sensitive teeth. The drug substance cansimply be a small amount of the active ingredient in a desensitizingtoothpaste or gel, such as Sensodyne®. The desensitizing agent isdispersed throughout the surface of the appliance and is delivered, at asubstantially constant rate, to the patient's sensitive teeth for arelatively extended period of time. Although the appliance may bepre-loaded with the agent and ready for use upon removal from anypackaging, appliances that are not pre-filled or pre-loaded may requireloading prior or immediately prior to placing the appliance over theteeth. Loading may comprise placing the agent in a teeth-receivingcavity. As described previously, the cavities may be filled to anydesired level. When the appliance is positioned over the teeth, theteeth will directly contact the agent in the cavities as the teeth areinserted into the cavities. Alternatively, loading may comprise placingthe agent into an agent release reservoir in the appliance immediatelyprior to placing the appliance over the teeth. The agent will then elutefrom the reservoir into the oral environment when the appliance is inplace over the teeth. The elution rate may be controlled by a controlledrelease membrane which separates the reservoir from the surroundingenvironment. Loading may also comprise adhering a rate controllingmaterial containing the agent to a surface of the appliance prior toplacing the appliance over the teeth. Such a material may comprise apolymer matrix membrane which may be removably or permanently adhered tothe polymeric shell of the appliance in desired areas for delivery ofthe agent. And finally, loading may comprise absorbing the agent into aporous material on or within the appliance immediately prior to placingthe appliance over the teeth.

Repositioning of the teeth with the use of a position adjustmentappliance involves placing the appliance over the teeth. However, theappliance is periodically removed for daily dental hygiene practices andother events throughout the repositioning protocol until the teeth aremoved to at least near the desired tooth arrangement. While theappliance is removed from the teeth, the appliance may be replenishedwith the agent or substance for delivery. Replenishment may be performedimmediately prior to each time the appliance is replaced over the teethor it may be performed according to any prescribed protocol.

In another aspect, methods for introducing agent delivery to aprescribed tooth repositioning treatment plan are provided. A treatmentplan is determined by an orthodontist or practitioner at the outset oforthodontic treatment. The plan involves moving the teeth through aseries of intermediate configurations or arrangements to a final desiredarrangement with the use of a system of tooth positioning appliances.Each appliance comprises a polymeric shell having cavities which isremovably placeable over the teeth and wherein the cavities ofsuccessive shells are shaped to reposition teeth from one arrangement toa successive arrangement according to the treatment plan. The entireseries of appliances may be provided at the outset of treatment, or asubset of appliances. In any case, the need or desire for delivery of anagent to the oral environment may occur at any point during the courseof treatment. In such a case, an agent and/or means for releasing anagent to the oral environment may be coupled to an appliance at any timeduring treatment.

Means for releasing the agent may include a number of embodiments,including any such means previously described. Typically, means forreleasing the agent comprises a layer including the agent, as previouslydescribed, and coupling comprises adhering the layer to at least aportion of a surface of the appliance. When the layer consistsessentially of the agent, adhering may involve coating, spraying,dipping or painting the agent on the surface of the appliance. Thus, apre-formed appliance may simply be coated with the agent prior toinsertion in the patient's mouth. When the layer comprises an agentpresent in or on a carrier or binder, adhering may involve attaching thecarrier or binder a surface of the appliance. Similarly, when the agentis encapsulated in the layer, the layer may be attached to the surfaceof the appliance. The layer may comprise a sheet of rate controllingmaterial wherein the rate controlling material controls the rate atwhich the agent is released from the layer. In this case, the sheet maybe bonded to the surface of the appliance with an adhesive.Alternatively, the sheet may be attached to the surface by pressfitting. The sheet and the surface may each be shaped so that they snapor fit together by pressing them together. For example, the sheet mayhave a formed protrusion and the surface a formed inset, wherein theprotrusion fits into the inset when pressed upon the inset and holds thesheet in place. In many instances, the appliance may be porous or have areservoir which can be loaded with a desired agent at any time thetreating professional and/or the patient decide that it is appropriate.For example, an appliance can be immersed in a solution of the agent,allowing the appliance to absorb or adsorb the agent at a particulartime.

In addition, the sheet may be pre-formed to a shape adapted for fittingagainst the surface of the appliance or a surface of the teeth orgingiva. For example, the sheet may be pre-formed to reflect the shapeof the surface of one or more teeth or the gingiva, particularly alongthe gingival margin. The preformed sheet may then be held against thatsurface when the sheet is coupled to the appliance and the appliance isplaced over the teeth. Coupling may involve any means of attaching thesheet to the appliance. In particular, the pre-formed sheet may furthercomprise an adhesive layer which may provide bonding of the sheet to thesurface of the appliance.

The material to make the appliance of FIG. 2A can be supplemented withadditional fillers such as electrically conducting fillers, magneticfillers, illuminating fillers, piezoelectric fillers, and/or lightsensitive fillers. The material properties of the appliance made with orwithout these additional fillers such as modulus, electrical resistance,material permeability, and birefringence (degree of orientation of thematerial or stress), illuminating patterns or patterns under speciallight sources may change after the appliance is worn over time, as theseproperties are altered due to changes in structure, organization, and/orspatial spacing between the fillers. For example, it is well establishedthat electrical conductivity of filled composites scales with fillervolume concentration according to percolation theory. Therefore,mechanical deformation or thermal expansion of the non-conductivepolymer matrix will lead to increased average inter-filler spacing, ordecreased filler volume concentration, and consequently decreasedelectrical conductivity. Examples of electrically conductive fillersinclude metals, graphite, electrically conductive polymers,semiconductors, and superconductors. These changes in properties can beused as an indicator for compliance and can be diagnosed byinstrumentation. Similarly, separation of conductive fillers will alsolower thermal conductivity, which can also be measured byinstrumentations. If the fillers have magnetic behavior in the presenceof external stimulation, such as diamagnetics (Cu, Au, Ag, etc.) andparamagnetics (e.g. Al, Cr, Na, Ti, Zr, etc.); or exhibit intrinsicmagnetic properties, such as ferromagnetics (Fe, Co, Ni, etc.),antiferromagnetics (e.g. MnO), and ferromagnetics (MFe₂O₄), thenseparation of the filler spacing due to mechanical deformation of thepolymer matrix can also lead to decreases in magnetic properties abovethe Curie temperature. Mechanical deformation of composites withilluminating fillers, such as those that exhibit luminescence,fluorescence, or phosphorescence, will result in decreased illuminationintensity. Bending deformation or displacement of piezoelectric fiberscan result in electrical potentials which can be either measured, orused to activate other electrically driven indicators (e.g. low powerLED light). Fillers with optical properties which depend on externalelectric field, for example those that shift their absorptioncoefficients in the UV, IR, or visible spectrum can also serve asindicators of matrix deformation.

FIG. 2B shows a second embodiment of FIG. 2A. In this embodiment, anappliance 17 has a plurality of delivery nozzles 18A-18C that projectfrom the appliance 17 to contact the patient's gum tissue on the side ofthe gum or in a periodontal pocket. The nozzles 18A-18C can be on eitherthe frontal side, the lingual side, or both sides of the teeth on thejaw 16. Optionally, one or more reservoirs 19A-19C can store extradrug/agent for delivery through nozzles 18A-18C. In one embodiment,reservoirs 19A, 19B, and 19C can contain the same drug or substance. Inanother embodiment, reservoirs 19A, 19B, and 19C can each contain adifferent drug/substance. In yet another embodiment, reservoir 19A and19C can contain the same drug and reservoir 19B can contain a differentdrug/substance. The combination of drug storage as discussed above isillustrative only and any suitable combination for storing a pluralityof drugs or substances in a plurality of reservoirs 19A-19C can be used.

FIG. 2C shows a cross-sectional view of the appliance of FIG. 2B on anexemplary tooth. As can be seen, the nozzle 18A either stores the drugor agent or receives drug/agent from the reservoir 19A. Moreover, thenozzle 18A is adapted to be inserted into the gum of the patient todeliver the drug/agent to the patient. FIG. 2D is a cross sectional viewof FIG. 2C without the tooth and gum line.

Referring now to FIG. 2E, another embodiment of a drug/agent deliverydevice is shown. In this embodiment, a plurality of drug/agentcontainers or modules 23 are positioned in an inside lining of aremovable dental appliance 21. The appliance 21 is fitted over a tooth25. During chewing or other oral activities, the appliance 21 carryingthe modules 23 is pressed toward the tooth 25. At a predeterminedpressure or force, one or more of the modules 23 burst, releasing thedrug or agent into the oral cavity. In addition to being positionedinside the lining of the appliance 21, the modules 23 can also bepositioned on an outside lining of the appliance 21 as well.

Turning now to FIG. 2F, yet another embodiment of a drug or agentdelivery device is shown. In this embodiment, an attachment 27 ismounted on a tooth 25. The attachment contains a first material that isinactive absent the presence of a second material. The second materialis coated on an appliance 29 and is also inactive in the absence of thefirst material. When the appliance 29 is worn over the tooth 25 and theattachment 27, the first and second materials react to form a drug or anagent suitable for intra-oral delivery.

Referring now to FIG. 3, another drug delivery system is shown. In thissystem, brackets and wires are used to effect tooth positioning as wellas drug delivery. On the frontal side of the teeth, a base 20 and aplurality of brackets 24 are positioned on the teeth. Additionally, awire 28 is positioned in the slots of the brackets 24. The base 20 andthe brackets 24 contain drug/agent to treat the patient.

In an alternative embodiment, the fixed appliances can be mounted on thelingual side of the teeth as well. For example, a base 30 and aplurality of brackets 34 are placed on the rear or lingual side of theteeth, and a wire 38 links the base and brackets for orthodontictreatment and drug delivery.

In yet another alternative embodiment, the drug/agent can be deliveredusing bases and brackets and wires on both sides of the teeth such asthat shown in FIG. 3.

Reservoirs can be positioned on the base and brackets to providetreatment drugs or agents. FIG. 4A shows a cross-sectional view whileFIG. 4B shows a perspective view of a bracket with a reservoir. As shownin FIGS. 4A-4B, a bracket body 42 has a base region 46 and a slot 47 toreceive a wire (not shown). Above the body 42 is a reservoir 44 thatcontains drugs or agents for delivery to the patient. The bracket body42 and reservoir 44 can be of any suitable metal, or can be of atranslucent or transparent plastic material or any suitablebiocompatible metal. These general types of materials are commonly usedin the practice of orthodontic care. It should be understood that thesize and shape of the bracket body 42 and reservoir 44 are not criticaland the exemplary bracket is described for purposes of illustration.

FIG. 4C shows another embodiment where the substance can be stored in acap 48 that is received by the slot 47. The cap 48 can be used with aconventional bracket without the reservoir 44 as well as with thebracket of FIG. 4A. When used with the bracket of FIG. 4A, the substancein the cap can be the same as the substance in the reservoir 44 or canbe different from the substance stored in the reservoir 44.

FIG. 4D shows yet another embodiment where the substance can be storedin a band 52 that encircles the slot 47. The band 52 can be used with aconventional bracket without the reservoir 44 as well as with thebracket of FIG. 4A. When used with the bracket of FIG. 4A, the substancein the band 52 can be the same as the substance in the reservoir 44 orcan be different from the substance stored in the reservoir 44.Optionally, the band 52 can receive a substance from a band reservoir54.

FIG. 4E shows yet another embodiment with a bracket 56 that has anopening 57 extending from one side of the bracket 56 to the other sideof the bracket 56. A substance is provided in a housing 58 which can beball-shaped or box-shaped, among others. A wire 59 is attached to thehousing 58 and the wire 59 can be threaded through the opening 57. Afterreaching the other side of the bracket 56, the wire can be twisted orbent or otherwise secured to the bracket 56, as shown by a bent wire59A. The bent wire secures the housing 58 to the bracket 56 for deliveryof substances to the patient.

FIG. 5A shows another embodiment where a second reservoir is mounted ona second side of the teeth opposite to the side where the bracket ofFIG. 4A is mounted. In this embodiment, a second reservoir 50 containsadditional drugs or agents. The second reservoir 50 is connected to thereservoir 44 through a pipe 52 to replenish the drug or agent as needed.

In another embodiment, the reservoirs 44 or 50 can be recharged using aneedle to inject additional drug/agent to the reservoirs. Alternatively,the reservoir 44 or 50 can be replaceable to replenish the drug/agent.

FIG. 5B shows another embodiment where a bracket 64 is used as a mountor support for a drug/agent housing 66 on a tooth 60. In thisembodiment, the housing 66 abuts the gum or a surface of the oral cavityto expedite delivery of drug/agent to the patient's body.

FIG. 5C shows another embodiment where the bracket 64 is used as a mountor support for a drug/agent housing 68 on the tooth 60. In thisembodiment, the housing 68 is spaced apart from the gum or a surface ofthe oral cavity to delivery drug/agent to the patient's body.

FIG. 5D shows yet another embodiment for delivery of drug or therapeuticagent. A permeable implant 70 is mounted on the patient's gum 71. A postor abutment 73 with a screw or threaded end 72 is mounted on the implant70. A crown-shaped housing 74 contains a drug or agent that seeps orpermeates through the abutment 73 and the implant 70 to be delivered tothe patient's body.

FIG. 5E shows a screw embodiment where drug or agent is embedded in ascrew having a head 76 and a threaded portion 75. The screw is tappedinto the patient's gum where it delivers the drug or agent into thepatient's body. In addition to screws, microstaples can be used todeliver drugs to the body. Moreover, dentures and partial dentures canhave drug(s) or agent(s) embedded therein to deliver drug to thepatient's oral cavity or body. In addition, the drugs or agents can beembedded in spaces between teeth.

FIG. 6A shows another embodiment where energy is applied to an appliance78 to affect teeth movement or drug delivery. In this embodiment,electricity is stored in an energy source 83 such as a battery. A switch81 is used to deliver energy to the oral cavity. The switch 81 iscontrolled by electronics 79 such as a microcontroller. The electronics79 delivers a predetermined amount of energy to treat the patient or todeliver drug.

FIG. 6B shows another embodiment where energy is applied to wires 80 and82 to effect teeth movement or drug delivery. In this embodiment,electricity is stored in an energy source 88 such as a battery. A switch84 is used to deliver energy to the oral cavity through wires 80 and 82.The switch 84 is controlled by electronics 86 such as a microcontroller.The electronics 86 delivers a predetermined amount of energy to treatthe patient. The energy in one instance can be low-level electricalcurrent to promote healing at the bone level. In another instance wherethe energy source 88 is connected through switch 84 to a material suchas nichrome, the energy can be low level heat. In another instance wherethe energy source 88 is connected through switch 84 to a light emittingdiode (LED), the energy can be light and when the LED is in a lasingmode, the energy can be a laser beam. The energy can be a magnetic fieldin another instance where the energy source 88 is connected throughswitch 84 to an inductor.

Ultra-sound can be used as well where the energy source 88 is connectedthrough switch 84 to an ultrasound vibratory source or transducer. Thetransducers can be electronically activated to vibrate and emitultrasonic pulses to promote bone healing. In addition to healing thebone, some of the pulses penetrate the tooth and are returned to othertransducers on a sensor array. These echo or reflected pulse signals,after being detected by transducers on the array, can be collected,analyzed and compared to produce a recreation of the tooth or dentalstructure being examined. By collecting reflected or scattered signalsfrom as many angles as possible, the electronics will have sufficienttime-of-flight measurements to perform a tomographic computation tomodel or map the tooth volume.

Vibrations can be used to inflame or irritate the bone structures topromote tooth movement as well. In one embodiment, the appliance iscoated with a material that can expand and contract upon receipt of anelectrical stimulus. Electroactive polymer composites, fabricated froman organic filler possessing very high dielectric constant dispersed inan electrostrictive polymer matrix, can be used as dental actuators. Thecomposite can have a matrix made from electrostrictive poly(vinylidenefluoridetrifluoroethylene), an electroactive copolymer and a filler suchas an organic semiconductor, copper-phthalocyanine. The composite actsas artificial muscles. Upon actuation, they can repetitively contractand expand to create vibrations on the teeth to encourage teethmovement.

Alternatively, memory-materials such as nitinol can be used and thecontraction/expansion can be controlled. Heat, electrical, or microwaveenergy can be used on other materials to induce them to change state andto inflame or stress the bone/gum structure to induce teeth movement.

In another embodiment, a wire can be attached directly to the teeth orindirectly to the teeth using a removable appliance and the wire can berepetitively wound and unwound using a micro-motor. Such repetitivemovements apply stress that inflame or irritate the gum or bonestructure to enhance teeth movement.

Thus, as discussed above, FIGS. 6A-6B show that the substance (in thiscase battery 83 or 88) provides energy to the oral cavity. The energycan be physical, electric, light, heat, sound, magnetic orelectromagnetic energy.

In addition to injecting energy, the devices of FIGS. 6A-6B can be usedto irritate or inflame the oral structure. For instance, the devices canbe used to inflame gingival or the bone structure of the teeth toencourage teeth repositioning.

In another embodiment, the appliances can be used to enhance drugdelivery by using electrical current to induce drug movement. Forexample, the drug molecules can be transported between one electricalpole to another electrical pole. Another implementation provides apositive current on one side of the appliance, and a negative current onthe other side of the appliance to force the drug through the gum ordental tissue.

In another embodiment, the appliance induces a change in the polarity ofthe teeth. The tooth is normally negatively charged and the drug in theappliance is positively charged. Opposite charges attract and bond toeach other and the drug or agent can be attached to the tooth surface by“ionic bonding”.

In yet another embodiment, the appliance containing drug can beconfigured so that positively charged ions are transferred to the teeth.The tooth polarity changes from negative to positive. The positivelycharged tooth ions repel the positively charged ions from othersubstances. For example, plaque ions are repelled from tooth ions suchthat plaque can be removed from the oral cavity.

In yet another embodiment, the appliance applies submucosaliontophoresis to accelerate tooth movement. Iontophoresis stimulatesosteoclasts in the periodontal pression side and osteoblasts in thetension side.

Agents to Accelerate or Decelerate Movement

In one embodiment, the substance accelerates tooth movement by degradingthe matrix. Matrix degradation can be stimulated either directly orindirectly. Chemical agents may act as enzymes to directly breakdownstructural proteins in the matrix. Proteases degrade protein, elastasesdegrade elastin, collagenase degrades collagen, among others. Otherdrugs or hormones such as relaxin, estrogen, or nicotine may act oncells within the matrix and cause those cells to secrete endogenousmatrix degrading enzymes. Many of these naturally occurring enzymes areknown as matrix metalloproteases (MMPs) and in the periodontal spacethese enzymes include MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9. Theexpression and function of these enzymes is usually under tight control,in part, by a concomitant expression of a group of molecules known astissue inhibitors of matrix metalloproteases (TIMPs).

A large number of drugs have been developed to prevent matrix breakdown.These drugs are typically useful as anti-inflammatory agents oranti-cancer therapies. Some of these candidates have been used toprevent or treat periodontitis. A very few drugs are available tostimulate matrix breakdown and those are commonly used for indicationslike wound debridement, breakdown of blood clots, or stimulatinggastrointestinal digestion. Their utility in the setting of orthodonticremodeling would need to be tested in appropriate preclinical models.

One exemplary drug can be Granulex or Xenaderm™ whose active ingredientis trypsin. This drug is indicated for wound debridement, wound healing,or varicose vein treatment. This ingredient breaks down many differenttypes of protein. Alternatively, another active ingredient such ashyaluronidase can be used to degrade hyaluronan which is thought to havea role in resisting compressive forces in tissue. Also, elastase can beused to degrade elastin preferentially and may help to both accelerateremodeling and prevent relapse.

Another exemplary drug can be Alteplase or Activase® whose activeingredient is tissue plasminogen activator. These drugs are indicatedfor thrombolytic therapy. In the presence of a thrombus Activase bindsto fibrin and converts plasminogen to plasmin to stimulate fibrinolysis.These drugs may only work in the context of blood clots.

Examples of other exemplary drugs are Arco-Lase®, Creon®, Kutrase®,Kuzyme®, Ultrase®, and Viocase®, whose activity depends on a combinationof enzymes: amylolytic, proteolytic, celluloytic and lipase. These drugsare indicated for the treatment of gastrointestinal disorders due topoor digestion. The drug, Arco-Lase, comes in soft, mint flavoredtablets. All these drugs warn that they may irritate oral mucosa, whichmay be an indication that they could work to soften gum tissue as wellas degrade food proteins.

Examples of other exemplary drugs are Accuzyme®, Gladase®, and Panafil®whose active ingredient is papain. This drug is indicated for treatmentof wound debridement. Papain combined with urea dissolves non-viableprotein but supposedly leaves viable tissue intact.

Another exemplary drug can be Potaba® whose active ingredient isaminobenzoate potassium. This drug is indicated for antifibrosis therapyfor scleroderma, Peyronie's disease, dermatomyositis and morphea. Thisingredient is part of the vitamin B complex and is reported to softentissue with long term use.

Another exemplary drug can be Aldurazyme® or Laronidase, whose activeingredient is alpha-L-iduronidase. This drug is indicated for treatmentof mucopolysaccharidosis. This ingredient is a lysosomal hydrolase thatbreaks down the glycosaminoglycans: dermatin sulfate and heparansulfate.

Another class of enzymes that may help to loosen gum tissue for thepurpose of accelerating tooth movement is the elastase family of enzymesthat break down elastin. Addition of these enzymes or induction ofendogenous elastase activity could also serve to prevent tooth relapsefollowing successful orthodontic tooth movement. Elastase enzymes areproduced by a number of inflammatory cells for example neutrophilelastase, leukocyte elastase, granulocyte elastase or macrophageelastase (which is also called MMP-12). As described below, agents oractivities that stimulate inflammation, cause an increase in the localconcentration of these inflammatory cells and therefore an increase inthe local concentration of elastase enzymes.

Additional enzymes that would also augment tissue degradation includehyaluronidase and cathepsin. Hyaluronidase is an enzyme found in mucousmembranes that specifically degrades hyaluronic acid which is part ofthe glycosaminoglycan matrix molecules important for resistingcompressive force. The cathepsin family of lysosomal enzymes is a largeand varied family of cystein proteases important in many diseaseprocesses that involve tissue disruption. Cathepsin B, for example, isknown to play a role in demyelination, emphysema, rheumatoid arthritisand neoplastic infiltration. Cathepsin B is also known to be elevated ingingival crevicular fluid during orthodontic tooth movement and isthought to be involved in extracellular matrix degradation in responseto mechanical stress. Another cathepsin, cathepsin K, is upregulated inodontoclasts and osteoclasts during tooth movement and may play a rolein root resorption during this process.

In general, the addition of any enzyme that is capable of breaking downa component of the gingival extracellular matrix is capable ofaccelerating tooth movement. An alternative means to disrupt the tissuematrix is by addition of compounds that can interfere with the normalinteraction between different components of the matrix architecture. Forexample, a family of proteins known as integrins serve to link cells tothe extracellular matrix. Addition of a class of agents known asdisintegrins can block this interaction and loosen the connectivestructure of the matrix. Disintegrins are found in snake venoms and areuseful to this species because of their ability to facilitate tissuepenetration of the venom. Disintegrins found in many snake species arecalled variously albolabrin, applagin, batroxostatin, bitistatin,echistatin, elegantin, flavoridin, halysin, kistrin, triflavin, andtrigramin.

Primary constituents of the extracellular matrix are collagen, elastin,fibronectin, laminin, integrins, proteoglycans and glycosaminoglycans.Additional constituents are fibrillin, versican, link protein, entactin,tenascin, vitronectin, decorin, cadherin and many others. Many of thesecomponents bind to one another to add rigidity and structural integrityto the tissue matrix architecture. Often these interactions are throughspecific binding sites involving an RGD (arginine-glycine-aspartate)peptide sequence. Antibodies or other binding agents that target thesebinding sites are capable of disrupting matrix integrity and looseningthe tissue. Specific antibodies have been developed to all of thesematrix proteins, though only the subset of enzymes that target epitopesimportant in protein-protein interactions are likely to cause tissuematrix disruption. Antibodies or other binding agents will be effectiveif they have an affinity for the binding sites that is greater than thatof the native proteins. One means of generating a large number of agentscapable of binding at, for example, an RGD site is by screening withphage display peptide libraries such as described in Odermatt et al.

Tissue extracellular matrix degradation may be brought about by directapplication of enzymes and binding agents as described above, or throughindirect means by addition of agents that stimulate the overexpressionof endogenous enzymes. An example of this type of agent includes drugsthat alter the expression or activity of matrix metalloproteases (MMPs).MMPs are a family of structurally related, protein-degrading enzymesthat require calcium ions for structural conformation and zinc ions intheir active site for function. The MMP enzymes can be administeredeither alone or in combination to directly impact tissue degradation. Asmentioned previously, MMP-1, MMP-2, MMP-3, MMP-8 and MMP-9 are thematrix degrading enzymes known to be active in the periodontal space.Matrix metalloproteases are also known as matrix metalloproteinases,collagenases, gelatinases, or CLGs. For example, depending on thenomenclature used, MMP-2 is also called collagenase type 4 (A),gelatinase A, or CLG 4 (A). Some MMPs are known by additional names dueto the fact that their discovery preceded knowledge of the familycharacteristics. For example, MMP-3 is also known as stromelysin-1 ortransin. The MMP enzymes listed above have been purified and areavailable commercially.

Collectively, the MMP family of enzymes is capable of digesting almostall of the components of the extracellular matrix. They often work bestin concert whereby an MMP isotype with selective collagenase activitywill cleave the type 1 collagen triple helix allowing access toadditional MMP enzymes which then further degrade the protein. MMP-3, incontrast to MMP-1 and MMP-2 does not break down type I collagen but candegrade proteoglycan and fibronectin which are other importantconstituents of the extracellular matrix. As they occur naturally inperiodontal tissue MMP activity is finely balanced by the presence ofendogenous enzyme inhibitors known as tissue inhibitors ofmetalloproteases (TIMPs). Adding exogenous MMPs to the tissue can alterthe balance of activity to bring about relatively more matrixdegradation and tissue disruption that may aid in tooth movement.

An exemplary drug that may work to accelerate tooth movement bystimulation of endogenous MMP activity is Prepidil® (dinoprostone) whoseactive ingredient is prostaglandin E2. This drug is indicated fortreatment of induction of labor. Prostaglandin E2 has been shown toenhance MMP-1 (collagenase) and sometimes MMP-3 (stromelysin) expressionin human gingival tissue. Another exemplary drug that contains the sameactive ingredient is Prostin E2® which is indicated for termination ofpregnancy.

Another exemplary drug can be Fluprostenol. This drug is a potentluteolytic agent with prostaglandin F2alpha activity. Research showsthat it can increase MMP-1 production and degrade connective tissue inhuman gingiva.

Another exemplary drug can be Nicoderm®, Commit® and Nicorette®, whoseactive ingredient is nicotine. This drug is indicated for treatment ofsmoking cessation. This ingredient has many effects such asvasodilation, but research shows it can increase collagenase activityand matrix turnover in gingival tissue.

Another example of an agent that stimulates the overexpression ofendogenous enzymes is keratinocyte-derived collagenase stimulatoryfactor also known as stratifin. Delivery of this agent can causeupregulation of collagenase enzymes in fibroblasts present in gingivaltissue. An even more direct way to stimulate overexpression of matrixdegrading enzymes is to use gene therapy techniques to either transfectlocal cells with constructs encoding these enzymes or with enhancer orpromoter elements capable, of stimulating endogenous gene transcriptionof those particular enzymes. For example, overexpression of manganesesuperoxide dismutase is known to cause activation of MMP-2. Agents thatelevate the intracellular concentration of cyclic adenosinemonophosphate (cAMP) are also capable of promoting MMP-2 overexpression,increasing the activity of this enzyme and decreasing collagen contentin tissue. Examples of agents with this capability are isoproterenol,prostaglandin E2 and forskolin. Relaxin is another agent that is capableof enhancing MMP-2 production.

In general any agent that triggers an inflammatory response can bringabout stimulation of MMP overexpression and matrix degradation. Anotherlarge family of molecules of interest in this regard is the cytokinefamily of molecules. Cytokines are agents usually secreted by cells tobring about a response in another cell. Thus, they are important in cellto cell communication. A number of common inflammatory cytokines havebeen elucidated and many more are likely to be discovered andcharacterized in the future. Inflammatory cytokines are released afterinjury and help to recruit additional inflammatory cells into the areaof tissue damage. Orthodontic tooth movement usually involves a mildinflammatory response. If exacerbated, this inflammatory response willlikely promote additional tissue degradation and may speed the processof tooth movement. The most commonly known inflammatory cytokines areinterleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha(TNFa) and transforming growth factorbeta (TGF-β).

There are many ways to stimulate an inflammatory response beyond directaddition of inflammatory cytokines. Inflammation can be brought about byvirtually any means of causing local tissue damage. Mechanical forcesuch as pushing, pulling or stretching the tissue can trigger release oflocal pro-inflammatory cytokines. Tearing or abrasion of either softtissue or bone can similarly trigger an inflammatory reaction. Additionof an irritant such as a powder, polymer, or any type of foreign bodycan incite inflammation. Alteration of local pH into either an acidic orbasic range beyond normal physiological pH can cause inflammation.Elevated temperature can have a similar effect as can the addition ofother energy sources such as ultrasound, or electrical energy.

Regardless of what means is used to stimulate the activation of localtissue degrading enzymes there is a need for limiting this activation soas not to cause significant and irreversible tissue damage. What issought is a mild enhancement of the inflammatory response normallyassociated with orthodontic tooth movement. The ability and mechanismsby which these limitations can be established will depend on the stimuliused to enhance inflammation. If agents or enzymes are administereddirectly, their activity can be controlled by monitoring thedose-response relationship and choosing the most appropriateconcentration. If indirect stimulators of endogenous enzymes are usedthen the tissue itself may provide some regulatory feedback (e.g.upregulation of TIMPs) to modulate and limit the overall response. Theultimate goal in this case is to strike the right balance to bring aboutmoderate tissue disruption.

In one implementation, the drug or bioactive agent assists in a“retention” phase, without which there is a tendency for the teeth toreturn to their initial position (relapse). The underlying cause forthis relapse appears to reside in the gingival tissue which, unlike boneand the PDL, is not resorbed during orthodontic treatment but iscompressed and consequently retracts. On the pressure aspect of thegingiva there is an increase in the number and size of elastic fibersand an increase in collagen. The elastic forces stored in the compressedgingiva can exert pressure on the tooth and cause relapse after therelease of retention. Procedures such as gingival circumferentialfiberotomy have been introduced to disconnect the compressed gingivafrom the tooth and have demonstrated some success in preventing toothrelapse.

Bioactive agents can accelerate tooth movement. The bioactive agentsdescribed above work primarily by enhancing collagen or elastindegradation. If delivered to the appropriate local tissue bed theseagents should, then, limit the increase in collagen and elastinaccumulation on the pressure side of the gingiva and reduce the tendencyto relapse. There are, however, other mechanisms to prevent toothrelapse. One way to chemically stabilize tooth position after completionof the orthodontic movement involves increasing the number of chemicalcrosslinks between collagen fibers, particularly on the tension aspectof the tooth. Increased crosslinking provides more structural stabilityto the new fiber orientation in the gingival tissue. Formaldehyde andglutaraldehyde are the most well known agents capable of crosslinkingcollagen and these agents are commonly used to treat bioprosthetictissue prior to use of that tissue as a medical implant. Standardformulations of formaldehyde and glutaraldehyde are likely too toxic tobe used in situ, but may be modified to reduce their tissue toxicity.

Chemical crosslinking agents can be used to crosslink extracellularmatrix components for many different indications. For example, Genipinis a relatively nontoxic, naturally occurring crosslinking agent thatcan be used. Carbodiimide is considered to be a somewhat less toxiccrosslinking agent, though at least one study showed that genipin wasbetter able to stimulate intermolecular collagen crosslinks compared tocarbodiimide. Intermolecular rather than intrahelical crosslinks aremore likely to bring about the desired tissue stabilization.1,6-diaminohexane (DAH) is also an effective collagen crosslinking agentthat has been shown to be slightly less toxic than cardodiimideespecially in the presence of glycosaminoglycans (which are naturallyoccurring in gingival tissue). Dimethyl 3,3′-dithiobispropionimidate isyet another example of a crosslinking agent reported to be morebiocompatible than standard agents like glutaraldehyde

Another class of compounds that may be useful is the reducing sugarsincluding glucose, ribose and derivatives of these sugars. The slowcrosslinking reaction between reducing sugars and biological aminesleads to the development of advanced glycation endproducts (AGEs). AGEsaccumulate over the course of a person's lifespan and a number ofdetrimental conditions have been attributed to this accumulationincluding increased vascular and myocardial stiffness, endothelialdysfunction, altered vascular injury responses and atheroscleroticplaque formation. In the setting of orthodontic applications, however,increased crosslinking for a limited period of time could provebeneficial and these agents are relatively simple sugars not associatedwith any additional toxicity. Acceleration of AGE-related crosslinkingcan be brought about by increasing the concentration of reducing sugarsand also by application of external energy such as UV irradiation.

The bioflavonoids is another broad class of compounds that could provevery useful in this endeavor. They are exemplified by molecules such asriboflavin, catechin and rutosides. Many of these compounds are foundnaturally in food substances like red wine and green tea. They tend tobe very biocompatible but are also known to promote the crosslinking ofcollagen either alone or in combination with adjunctive energy like UV-Aor rose Bengal/white-light irradiation. In the case of riboflavin-UVA,this treatment has been used clinically to promote collagen crosslinkingof the sclera to increase its biomechanical strength for the treatmentof progressive myopia.

Although it appears that the accumulation of extracellular matrixproteins in gingival tissue has an important role in tooth relapse,there is also evidence that bone remodeling plays a part. Experimentaldata from the School of Dentistry in Tohoku University, Japan, showedthe ability of a bisphosphonate (risedronate) to prevent tooth relapse.Risedronate is a potent blocker of bone resorption. When appliedtopically during the phase of orthodontic tooth movement, it reducedtooth movement. When applied during the retention phase, it was able toinhibit relapse.

In another embodiment, the substance can be anesthetics and analgesicssuch as benzocaine, lidocaine and prilocaine, among others, that arelocally released through the appliance. These substances may promotepatient compliance for appliance usage/wear, and also for the palliativerelief of oral discomfort due to intraoral ulcers, cancer sores, andother lesions associated with trauma, disease, or surgical procedures.

In yet another embodiment, the drug can be nicotine to relieve patientdiscomfort or to treat another disease. As discussed in U.S. Pat. No.4,215,706, the content of which is incorporated by reference, tobacco(donor tobacco) is contacted with a receiving substrate on the appliancewhich has been treated with a strong acid or an ammonium salt of astrong acid. Part of the nicotine in the donor tobacco is transferredfrom the donor tobacco to the receiving substrate. Thereafter the donortobacco and the substrate may be separated. The donor tobacco has areduced nicotine content for pain relief or medical treatment.

In yet another embodiment, the appliance can be used to provide a localrelease of breath fresheners such as menthol, peppermints, spearmints,wintergreen, zinc gluconate, citrus, clove and thymol, among others,that may promote patient compliance to facilitate treatment. More breathfreshener information is shown in US Patent Publication No. 20040115137,the content of which is incorporated by reference.

Additionally, the substance can prevent tooth decay through fluoridetreatment. Treatments include toothpastes, gels, rinses and varnishes.Gum disease, such as gingivitis or periodontitis, is caused by bacterialgrowth associated with dental plaque and calculus deposits. The mostcommon recommendation for preventing such bacterial growth is tomechanically remove the plaque from the tooth surfaces. However, chronicgingivitis and tooth decay have plagued many individuals who in factcomply with good oral hygiene methods and plaque removal. This may bedue to a variety of factors including genetic predispositions,illnesses, mouth breathing, and medical treatment programs. In suchcases, bacterial control may be accomplished with the use ofantibacterial drugs. A common antibacterial agent shown to be effectivein reducing the activity of many common strains of oral flora ischlorhexidine. Chlorhexidine is a cationic biguanide microbicide with abroad spectrum of activity against many forms of bacteria and fungi.Therefore, it has been a popular agent in many studies of gingivitisreversal. Chlorhexidine has traditionally been delivered to the oralenvironment through the use of rinses, such as Peridex® (Proctor andGamble). Sustained delivery to the gingiva has also been attempted withthe use of chlorhexidine impregnated dental floss and dental appliances,such as trays or mouthguards. Another frequently prescribedantibacterial agent is tetracycline. Tetracycline is a broad spectrumantibiotic which is effective against virtually all common groups ofpathogenic bacteria, both gram positive and negative. Tetracycline maybe combined with an antifungal agent, such as amphotericin, to provideactivity against fungi. Tetracycline has traditionally been delivered tothe oral environment through systemic administration, although localizeddelivery has been attempted with the insertion of tetracycline-filledhollow fiber devices into periodontal pockets and the use oftetracycline laden dental appliances, such as trays and mouthguards. Inaddition, a number of other antibacterial drugs are available for dentaland periodontal therapy.

Cosmetic treatments often include tooth bleaching or whitening andbreath freshening products. Discolorations of enamel and dentin mayoccur due to aging, consumption of staining substances (coffee, tea,colas, tobacco), trauma, staining due to systemic tetracycline(antibiotic) therapy, excessive fluoride, nerve degeneration and olddental restorations. Bleaching lightens these discolorations for awhiter or brighter appearance. Typically, a bleaching gel is placed in athin custom-fitted tray that fits over the teeth. The tray is worn atnight for usually 10 to 14 days and may require periodic rebleachingtreatments for approximately one or two nights every six months. Breathfreshening products are often used by patients to treat halitosis or forenjoyment of the taste. These include a variety of sprays, rinses,mints, gums, or candies, to name a few.

Additionally, the substance can include chemicals that irritate the gumor bone. Alternatively, the substance can inflame a bone.

Often the use of a combination of drugs or bioactive agents can impartmore benefit than the use of any single agent. The appliance used todeliver therapeutic or cosmetic agents to oral tissue can be easilyadapted to deliver more than one agent and can also be adapted todeliver specific agents to select locations within the oral tissue. Forexample, a drug that accelerates collagen and/or elastin degradationmight be delivered to the pressure aspect of the gingiva where there istypically an increase in the number and size of collagen and elasticfibers that oppose tooth movement. Simultaneously, the appliance mightdeliver an agent that promotes the crosslinking of collagen to thetension aspect of the gingiva to help stabilize the tooth movementachieved with the appliance. In one embodiment, reservoirs 19A, 19B, and19C (FIG. B) can contain the same drug or substance. In anotherembodiment, reservoirs 19A, 19B, and 19C can each contain a differentdrug/substance. In yet another embodiment, reservoir 19A and 19C cancontain the same drug and reservoir 19B can contain a different drug.Thus, in one example bleaching agents can be stored in one reservoir anddelivered to the tooth itself while a second reservoir can store anddeliver an agent capable of accelerating tooth movement to the gingivasurrounding the tooth.

Just as different agents need not be delivered to identical locationswithin the oral tissue, different agents need not be delivered at thesame time. It may be advantageous to deliver one agent at the beginningof orthodontic treatment and a different agent at another point duringthe treatment. An example of this treatment regimen would be delivery ofagents to accelerate tooth movement during the first weeks oforthodontia and delivery of agents to prevent tooth relapse followingthe period of tooth movement.

In some cases it is necessary to add one agent to modify the activity ofanother agent. For example, a buffering agent may be needed to alter thepH of a drug so as to make the therapeutic agent less caustic. Inanother case it might be necessary to add one agent to stabilize oractivate the therapeutic agent once it has been released from theappliance. An alternative exemplary case would be the use of more thanone agent that have the same general effect as, for example, two agentsthat are likely to accelerate tooth movement. Two or more agents may beemployed rather than one either because they will act synergistically byemploying different modes of action to bring about an effect or becausethey have different unwanted side effects that can be reduced by lowingthe dose delivered of each but maintaining a beneficial therapeuticeffect because of the ability of the agents to work together in concert.

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow. Forexample, although films or appliances have been disclosed as mechanismsfor delivery drugs or substances, droplets can be used to deliversubstances to the patient as well. Typically, droplets can be sizedwithin the range of about 1 to 200 microns and may be presented to themucosa within a liquid, solid, or gaseous suspension, including anaerosol system which refers to a gaseous suspension of particlesdispensed within the form of a mist. Other embodiments for deliveringdrugs or substances can be used as well. Whereas particular embodimentsof the present invention have been described herein for purposes ofillustration, it will be evident to those skilled in the art thatnumerous variations of the details may be made without departing fromthe invention as defined in the appended claims.

What is claimed is:
 1. A device for delivering one or more substances,comprising: a dental device comprising a shell formed of a material andthe dental device configured to move a number of teeth and including oneor more reservoirs formed in the shell; at least one of the reservoirssupplied with the one or more substances; and a nozzle formed of thematerial as a portion of the shell and connected to the at least onereservoir and configured to be inserted into a gum of a patient tofluidly release the one or more substances from at least one reservoirat a first preselected dose at a first predetermined time period and tofluidly release the one or more substances from at least one reservoirat a second preselected dose at a second predetermined time period,wherein the nozzle is shaped to conform to the gum for prolongedplacement therein.
 2. The device of claim 1, wherein the one or moresubstances include a therapeutically effective amount of a drug or abioactive agent.
 3. The device of claim 1, wherein the one or moresubstances provide one or more results selected from the group ofresults including: accelerating tooth movement; decelerating toothmovement; accelerating tooth movement by degrading collagen in the oraltissue; accelerating tooth movement by degrading elastin in the oraltissue; accelerating tooth movement by increasing the expression ofendogenous enzymes that degrade collagen; accelerating tooth movement byincreasing the expression of endogenous enzymes that degrade elastin;accelerating tooth movement by increasing the activity of endogenousenzymes that degrade collagen; accelerating tooth movement by increasingthe activity of endogenous enzymes that degrade elastin; acceleratingtooth movement by causing degradation of glycosaminoglycans orproteoglycans; inducing irritation of the oral structure; inducinginflammation of a bone structure; inducing inflammation of surroundingtissue; inducing inflammation of a bone structure or surrounding tissueby increasing the local concentration of interleukin-1, interleukin-6,tumor necrosis factor-alpha, or transforming growth factor-beta;relieving oral pain involved with dental movement; relieving pain fromalveolar ridge augmentation and orthognathic treatment; providing freshbreath; altering tooth movement by stimulating bone resorption; alteringtooth movement by reducing bone resorption; and preventing tooth relapseby causing an increase in the number of crosslinks between tissue matrixproteins in the oral environment.
 4. The device of claim 1, furtherconfigured to deliver one of the one or more substances to a specificlocation within the gum and to deliver a different one of the one ormore substances to a different location within the gum.
 5. The device ofclaim 1, further comprising a supply of energy thereto.
 6. The device ofclaim 1, wherein the energy comprises electric, light, heat, sound,magnetic or electromagnetic energy.
 7. The device of claim 1, whereinthe device is configured to fluidly release the one or more substanceswithout active physical manipulation of the at least one reservoir. 8.The device of claim 1, wherein the device is designed from scans of thepatient's dentition.
 9. The device of claim 1, wherein the device isdesigned to dispense the one or more substances in a predeterminedsequence.
 10. The device of claim 1, wherein the device is designed todispense the substance in two or more different preselected dosages fordelivery at two or more different predetermined periods.
 11. The deviceof claim 1, further configured to sample an intra-oral substance in thepatient's mouth, whether the intra-oral substance has been delivered toor is already present in the mouth; and diagnose a body condition basedon a result of the intra-oral substance sample.
 12. The device of claim11, wherein the body condition comprises a disease.
 13. The device ofclaim 11, further configured to perform a close-loop delivery of thesubstance within the mouth based on the result of the intra-oralsubstance sample.
 14. The device of claim 11, further configured totransmit the result of the intra-oral substance sample to a remotecomputer for diagnosis.
 15. The device of claim 1, wherein at least oneof the one or more substances contains at least one of the followingactive ingredients: trypsin; elastase; papain; aminobenzoate potassium;cathepsin; amylolytic enzyme; proteolytic enzyme; celluloytic enzyme;lipase; prostaglandin E2; prostaglandin F2alpha; heparin; relaxin;conconavalen A; nicotine; hyaluronidase; alpha-L-iduronidase; catabolin;estradiol; genipin; carbodiimide; glutaraldehyde; formaldehyde;1,6-diaminohexane; bioflavonoids; or reducing sugars including glucose,ribose, or derivatives thereof.
 16. The device of claim 1, wherein atleast one of the one or more substances alters tooth movement bystimulating or reducing bone resorption.
 17. The device of claim 1,wherein at least one of the one or more substances contains abisphosphonate.
 18. The device of claim 1, wherein a first reservoir ofthe one or more reservoirs is supplied with a first substance of the oneor more substances and a second reservoir of the one or more reservoirsis supplied with a second substance of the one or more substances. 19.The device of claim 18, wherein the first substance is different fromthe second substance.
 20. The device of claim 18, wherein the firstsubstance is the same as the second substance.
 21. The device of claim18, wherein a third reservoir of the one or more reservoirs is suppliedwith a third substance of the one or more substances, wherein the firstand third substances are different from the second substance.
 22. Thedevice of claim 1, wherein one of the one or more substances comprisesanalgesics.
 23. The device of claim 1, wherein the nozzle is configuredto be inserted into the gum on a lingual side of the number of teeth.24. The device of claim 1, wherein the nozzle is configured to beinserted into the gum on a frontal side of the number of teeth.
 25. Thedevice of claim 24, wherein the dental device includes a second nozzleconfigured to be inserted into the gum on a lingual side of the numberof teeth.
 26. The device of claim 1, wherein a dispensing mechanism ofthe nozzle is chemically activated.
 27. The device of claim 1, wherein adispensing mechanism of the nozzle is electronically activated.
 28. Thedevice of claim 1, wherein the dental device includes a processorthereon for controlling a dispensing mechanism of the nozzle.
 29. Asystem for delivering one or more substances, comprising: a plurality ofappliances, comprising shells formed of a material, configured to move anumber of teeth of a patient, wherein at least one of the appliancesincludes: a reservoir formed in the shell; and a nozzle formed of thematerial as a portion of the shell, connected to the reservoir, andconfigured to be inserted into a gum of the patient to fluidly release asubstance from the reservoir at a first preselected dose at a firstpredetermined time period and to fluidly release the substances from thereservoir at a second preselected dose at a second predetermined timeperiod, wherein the nozzle is shaped to conform to the gum for prolongedplacement therein.
 30. The system of claim 29, wherein the plurality ofappliances are designed from scans of the patient's dentition.
 31. Thesystem of claim 30, wherein at least one of the plurality of appliancesis designed to dispense a plurality of substances in a predeterminedsequence.
 32. The system of claim 30, wherein two or more of theplurality of appliances are designed to dispense the substance in two ormore different preselected dosages for delivery at two or more differentpredetermined periods.
 33. The system of claim 29, wherein the reservoiris supplied with the substance.
 34. The system of claim 29, wherein thenozzle is configured to be inserted into the gum on a lingual side ofthe number of teeth.
 35. The system of claim 29, wherein the nozzle isconfigured to be inserted into the gum on a frontal side of the numberof teeth.
 36. The system of claim 35, wherein the at least one of theappliances includes a second nozzle configured to be inserted into thegum on a lingual side of the number of teeth.
 37. The system of claim29, wherein a dispensing mechanism of the nozzle is chemicallyactivated.
 38. The system of claim 29, wherein a dispensing mechanism ofthe nozzle is electronically activated.
 39. The system of claim 29,wherein the at least one appliance includes a processor thereon forcontrolling a dispensing mechanism of the nozzle.
 40. The system ofclaim 39, wherein the processor is configured to control the dispensingmechanism of the nozzle in a close-loop manner.
 41. The system of claim29, wherein the shell includes a cavity shaped to be removably placeableover a number of teeth.